tbuckley/cabot-search huggingface dataset:
Photobiomodulation attenuates oligodendrocyte dysfunction and prevents adverse neurological consequences in a rat model of early life adversity
Authors: Zhihai Huang, Yulan Zhang, Xiaohui Ma, Yu Feng, Xuemei Zong, J. Dedrick Jordan, Quanguang Zhang
Journal: Theranostics (2023)

Rationale: Adverse experiences in early life including abuse, trauma and neglect, have been linked to poor physical and mental health outcomes. Emerging evidence implies that those who experienced early life adversity (ELA) are more likely to develop cognitive dysfunction and depressive-like symptoms in adulthood. The molecular mechanisms responsible for the negative consequences of ELA, however, remain unclear. In the absence of effective management options, anticipatory guidance is the mainstay of ELA prevention. Furthermore, there is no available treatment that prevents or alleviates the neurologic sequelae of ELA, especially traumatic stress. Hence, the present study aims to investigate the mechanisms for these associations and evaluate whether photobiomodulation (PBM), a non-invasive therapeutic procedure, can prevent the negative cognitive and behavioral manifestations of ELA in later life. Methods: ELA was induced by repeated inescapable electric foot shock of rats from postnatal day 21 to 26. On the day immediately following the last foot shock, 2-min daily PBM treatment was applied transcranially for 7 consecutive days. Cognitive dysfunction and depression-like behaviors were measured by a battery of behavioral tests in adulthood. Subsequently, oligodendrocyte progenitor cells (OPCs) differentiation, the proliferation and apoptosis of oligodendrocyte lineage cells (OLs), mature oligodendrocyte, myelinating oligodendrocyte, the level of oxidative damage, reactive oxygen species (ROS) and total antioxidant capacity were measured and analyzed using immunofluorescence staining, capillary-based immunoassay (ProteinSimple®) and antioxidant assay kit. Results: The rats exposed to ELA exhibited obvious oligodendrocyte dysfunction, including a reduction in OPCs differentiation, diminished generation and survival of OLs, decreased OLs, and decreased matured oligodendrocyte. Furthermore, a deficit in myelinating oligodendrocytes was observed, in conjunction with an imbalance in redox homeostasis and accumulated oxidative damage. These alternations were concomitant with cognitive dysfunction and depression-like behaviors. Importantly, we found that early PBM treatment largely prevented these pathologies and reversed the neurologic sequelae resulting from ELA. Conclusions: Collectively, these findings provide new insights into the mechanism by which ELA affects neurological outcomes. Moreover, our findings support that PBM may be a promising strategy to prevent ELA-induced neurologic sequelae that develops later in life.
A plan to improve global type 1 diabetes epidemiology data
Authors: David Beran, Kurt Højlund, Stéphane Besançon, Mads Loftager Mundt, Graham D Ogle, Kaushik Ramaiya, Tom Robinson, Jannet Svensson, Jaakko Tuomilehto, Sarah Wild, Anders Green
Journal: The Lancet Diabetes & Endocrinology (2023)
BNT162b2 antigen dose and SARS-CoV-2 omicron infection in adolescents
Authors: Hiam Chemaitelly, Houssein H Ayoub, Peter Coyle, Patrick Tang, Hadi M Yassine, Asmaa A Al Thani, Hebah A Al-Khatib, Mohammad R Hasan, Zaina Al-Kanaani, Einas Al-Kuwari, Andrew Jeremijenko, Anvar Hassan Kaleeckal, Ali Nizar Latif, Riyazuddin Mohammad Shaik, Hanan F Abdul-Rahim, Gheyath K Nasrallah, Mohamed Ghaith Al-Kuwari, Hamad Eid Al-Romaihi, Adeel A Butt, Mohamed H Al-Thani, Abdullatif Al-Khal, Roberto Bertollini, Laith J Abu-Raddad
Journal: The Lancet Infectious Diseases (2023)
Saliva-based microfluidic point-of-care diagnostic
Authors: Trey W. Pittman, Daniel Balazs Decsi, Chamindie Punyadeera, Charles S. Henry
Journal: Theranostics (2023)

There has been a long-standing interest in point-of-care (POC) diagnostics as a tool to improve patient care because it can provide rapid, actionable results near the patient.Some of the successful examples of POC testing include lateral flow assays, urine dipsticks, and glucometers.Unfortunately, POC analysis is somewhat limited by the ability to manufacture simple devices to selectively measure disease specific biomarkers and the need for invasive biological sampling.Next generation POCs are being developed that make use of microfluidic devices to detect biomarkers in biological fluids in a non-invasive manner, addressing the above-mentioned limitations.Microfluidic devices are desirable because they can provide the ability to perform additional sample processing steps not available in existing commercial diagnostics.As a result, they can provide more sensitive and selective analysis.While most POC methods make use of blood or urine as a sample matrix, there has been a growing push to use saliva as a diagnostic medium.Saliva represents an ideal non-invasive biofluid for detecting biomarkers because it is readily available in large quantities and analyte levels reflect those in blood.However, using saliva in microfluidic devices for POC diagnostics is a relatively new and an emerging field.The overarching aim of this review is to provide an update on recent literature focused on the use of saliva as a biological sample matrix in microfluidic devices.We will first cover the characteristics of saliva as a sample medium and then review microfluidic devices that are developed for the analysis of salivary biomarkers.
To Cool or Not to Cool — Organ-Preservation Strategies in Transplantation
Authors: Paulo N. Martins, Winfred W. Williams
Journal: New England Journal of Medicine (2023)

A major unmet need in deceased-donor organ transplantation is improved organ preservation, a process that involves enormous logistic constraints and financial costs. On the basis of a study by Niemann et al.1 on the protective effects of mild hypothermia in deceased-donor kidneys, Axelrod2 and investigators from the Niemann group conducted a subsequent economic modeling study that assumed an absolute reduction in the incidence of delayed graft function of 25 percentage points among extended-criteria donors and of 7 percentage points among standard-criteria donors. They posited that as compared with standard static cold storage, a cooling protocol that resulted in these reductions . . .
Genome editing with natural and engineered CjCas9 orthologs
Authors: Siqi Gao, Yao Wang, Tao Qi, Jingjing Wei, Ziying Hu, Jingtong Liu, Shuna Sun, Huihui Liu, Yongming Wang
Journal: Molecular Therapy (2023)

CjCas9 is one of the smallest CRISPR-associated (Cas9) nucleases for mammalian genome editing. However, it requires a long N
Exosomal STIMATE derived from type II alveolar epithelial cells controls metabolic reprogramming of tissue-resident alveolar macrophages
Authors: Zunyong Feng, Zhou Jing, Qiang Li, Liuxi Chu, YuXin Jiang, Xuanbo Zhang, Liang Yan, Yinhua Liu, Jing Jiang, Ping Xu, Qun Chen, Ming Wang, Hui Yang, Guoren Zhou, Xiaochun Jiang, Xiaoyuan Chen, Hongping Xia
Journal: Theranostics (2023)

Background: Complete abolition of alveolar epithelial cells (AECs) is characteristic of end-stage lung disease.Transplantation therapy of type II AECs (AEC-IIs) or AEC-IIs-derived exosomes (ADEs) have been proposed as a means of repairing injury and preventing fibrosis.However, the mechanism by which ADEs balances airway immunity and alleviates damage and fibrosis remains unknown.Methods: We investigated STIM-activating enhancer-positive ADEs (STIMATE + ADEs) in the lung of 112 ALI/ARDS and 44 IPF patients, and observed the correlation between STIMATE + ADEs and subpopulation proportion and metabolic status of tissue-resident alveolar macrophages (TRAMs).We constructed the conditional knockout mice STIMATE sftpc , in which STIMATE was specifically knocked out in mouse AEC-IIs and observed the effects of STIMATE + ADEs deficiency on disease progression, immune selection and metabolic switching of TRAMs.We constructed a BLM-induced AEC-IIs injury model to observe the salvage treatment of damage/fibrosis progression with STIMATE + ADEs supplementation.Results: In clinical analysis, the distinct metabolic phenotypes of AMs in ALI/ARFS and IPF were significantly perturbed by STIMATE + ADEs.The immune and metabolic status of TRAMs in the lungs of STIMATE sftpc mice was imbalanced, resulting in spontaneous inflammatory injury and respiratory disorders.STIMATE + ADEs are taken up by tissue-resident alveolar macrophages TRAMs to regulate high Ca 2+ responsiveness and long-term Ca 2+ signal transduction, which maintains M2-like immunophenotype and metabolism selection.This involves calcineurin (CaN)-PGC-1α pathway mediated mitochondrial biogenesis and mtDNA coding.In a bleomycin-induced mouse fibrosis model, supplementation with inhaled STIMATE + ADEs lessened early acute injury, prevented advanced fibrosis, alleviated ventilatory impairment and reduced mortality.
Efficacy and safety of the SGLT2 inhibitor empagliflozin versus placebo and the DPP-4 inhibitor linagliptin versus placebo in young people with type 2 diabetes (DINAMO): a multicentre, randomised, double-blind, parallel group, phase 3 trial
Authors: Lori M Laffel, Thomas Danne, Georgeanna J Klingensmith, William V Tamborlane, Steven Willi, Philip Zeitler, Dietmar Neubacher, Jan Marquard, Tatiana Bardymova, Margarita Barrientos Perez, Kathleen Bethin, Petter Bjornstad, Irina Bondar, Mimi Chen, Jin-Ho Choi, Mark A Clements, Javier Ricardo Colomar, Mark Daniels, Chaicharn Deerochanawong, Vivek S Desai, Jean-Claude G Desmangles, Robert G Dillon, Naznin M Dixit, Hongwei Du, Rachel Edelen, Diego Espinoza Peralta, María Verónica Felipe Gacioppo, Tania Maria Bulcão Lousada Ferraz, Galina Galkina, Mary Patricia Gallagher, Minu George, Edgar Gonzalez, Michael Everett Gottschalk, Giancarlo Guido, Amir Ali Hassan, Eli Hershkovitz, Lina P Huerta-Saenz, Jin Soon Hwang, Jaime Orlando Ibarra Gomez, Lydia Irizarry Gonzalez, Nina Jain, David H Jelley, Ho-Seong Kim, Tatiana Kovalenko, Lori Michelle B Laffel, Steven B Leichter, Raphael Del Roio Liberatore Jr, Jane Lynch, Farid Hussain Mahmud, Oleg Arturovich Malievskiy, Andrew Muir, Bryce A Nelson, Luis Alejandro Nevarez Ruiz, Micah L Olson, Emilia Susana Pelayo Orozco, Valentina Peterkova, Fernando Ramón Ramírez Mendoza, Konda Mohan Reddy, Henry Rodriguez, Javier Andres Saenz, Julia Samoilova, Karl-Otfried Schwab, Sejal H Shah, Naim Shehadeh, Ashley H Shoemaker, Yulia Skorodok, Aleksandr Sobolev, Silvana Ernestina Solís, Shylaja Srinivasan, William V Tamborlane, Eva Tsalikian, Farida Valeeva, Carl D Vance, Pedro A Velasquez-Mieyer, Rafael Margarito Violante Ortiz, Olga Votyakova, Haiyan Wei, Ruth S Weinstock, Mark D Wheeler, Brandy Alexandra Wicklow, Steven M Willi, Kupper A Wintergerst, Risa M Wolf, Jamie Ruth Wood, Chandan Yaliwal, Hernán Yupanqui Lozno
Journal: The Lancet Diabetes & Endocrinology (2023)
Obtaining the best igRNAs for bystander-less correction of all ABE-reversible pathogenic SNVs using high-throughput screening
Authors: Bo Li, Dongdong Zhao, Yaqiu Li, Yuanzhao Yang, Xiagu Zhu, Ju Li, Changhao Bi, Xueli Zhang
Journal: Molecular Therapy (2023)

Imperfect -gRNA (igRNA) provides a simple strategy for single-base editing of a base editor. However, a significant number of igRNAs need to be generated and tested for each target locus to achieve efficient single-base reversion of pathogenic single nucleotide variations (SNVs), which hinders the direct application of this technology. To provide ready-to-use igRNAs for single-base and bystander-less correction of all the adenine base editor (ABE)-reversible pathogenic SNVs, we employed a high-throughput method to edit all 5,253 known ABE-reversible pathogenic SNVs, each with multiple systematically designed igRNAs, and two libraries of 96,000 igRNAs were tested. A total of 1,988 SNV loci could be single-base reversed by igRNA with a >30% efficiency. Among these 1,988 loci, 378 SNV loci exhibited an efficiency of more than 90%. At the same time, the bystander editing efficiency of 76.62% of the SNV loci was reduced to 0%, while remaining below 1% for another 18.93% of the loci. These ready-to-use igRNAs provided the best solutions for a substantial portion of the 4,657 pathogenic/likely pathogenic SNVs. In this work, we overcame one of the most significant obstacles of base editors and provide a ready-to-use platform for the genetic treatment of diseases caused by ABE-reversible SNVs.
Exercise Intensity and Longevity in Men
Authors: I-Min Lee
Journal: JAMA (1995)

<h3>Objective.</h3> —To examine the independent associations of vigorous (≥6 resting metabolic rate [MET] score) and nonvigorous (&lt;6 MET score) physical activity with longevity. <h3>Design.</h3> —Prospective cohort study, following up men from 1962 or 1966 through 1988. <h3>Setting/Participants.</h3> —Subjects were Harvard University alumni, without self-reported, physician-diagnosed cardiovascular disease, cancer, or chronic obstructive pulmonary disease (n=17 321). Men with a mean age of 46 years reported their physical activities on questionnaires at baseline. <h3>Main Outcome Measure.</h3> —All-cause mortality (3728 deaths). <h3>Results.</h3> —Total energy expenditure and energy expenditure from vigorous activities, but not energy expenditure from nonvigorous activities, related inversely to mortality. After adjustment for potential confounders, the relative risks of dying associated with increasing quintiles of total energy expenditure were 1.00 (referent), 0.94, 0.95, 0.91 and 0.91, respectively (<i>P</i>[trend]&lt;.05). The relative risks of dying associated with less than 630,630 to less than 1680,1680 to less than 3150,3150 to less than 6300, and 6300 or more kJ/wk expended on vigorous activities were 1.00 (referent), 0.88, 0.92, 0.87, and 0.87, respectively (<i>P</i>[trend]=.007). Corresponding relative risks for energy expended on nonvigorous activities were 1.00 (referent), 0.89,1.00,0.98, and 0.92, respectively (<i>P</i>[trend]=.36). Analyses of vigorous and nonvigorous activities were mutually adjusted. Among men who reported only vigorous activities (259 deaths), we observed decreasing age-standardized mortality rates with increasing activity (<i>P</i>=.05); among men who reported only nonvigorous activities (380 deaths), no trend was apparent (<i>P</i>=.99). <h3>Conclusions.</h3> —These data demonstrate a graded inverse relationship between total physical activity and mortality. Furthermore, vigorous activities but not nonvigorous activities were associated with longevity. These findings pertain only to allcause mortality; nonvigorous exercise has been shown to benefit other aspects of health. (<i>JAMA</i>. 1995;273:1179-1184)
A phase 1/2 open-label study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of OTX-2002 as a single agent and in combination with standard of care in patients with hepatocellular carcinoma and other solid tumor types known for association with the MYC oncogene (MYCHELANGELO I).
Authors: Ildefonso I Rodriguez-Rivera, Ting-Hui Wu, Rachel Ciotti, William Senapedis, Kaitlyn Sullivan, Jeff Z Gao, Sangeetha Palakurthi, Thomas McCauley, Yan Moore
Journal: Journal of Clinical Oncology (2023)

TPS627 Background: MYC, or c-MYC, is a master regulator of gene expression that controls cell growth and proliferation. Dysregulation of MYC is frequently identified in various cancer types, including hepatocellular carcinoma (HCC), where it is overexpressed in up to 70% viral and alcohol-related disease. 1 While MYC represents an attractive therapeutic target, it has historically been considered undruggable due to a lack of a structured binding pocket and its tightly autoregulated expression. OTX-2002 is a first-in-class, engineered and programable mRNA therapeutic called Omega Epigenomic Controllers (OECs) that modulates MYC gene expression pre-transcriptionally by creating epigenetic marks at two different structural and regulatory elements within the insulated genomic domain where MYC resides. In vitro studies have demonstrated that downregulation of MYC through OTX-2002 led to loss of viability in HCC cells while sparing normal hepatocytes. In HCC xenograft mouse models, OTX-2002 demonstrated anti-tumor activity as monotherapy and in combinations with standard of care therapies in HCC. 2 Methods: OTX-2002 is being evaluated in an open-label, non-randomized, phase 1/2 study (MYCHELANGELO I) in patients with HCC and other advanced solid tumor types (NCT05497453). The study consists of two parts. Part 1 dose escalation explores ascending doses of intravenous OTX-2002 monotherapy given every 2 weeks to identify dose limiting toxicities, maximum tolerated dose, and recommended dose for expansion (RDE) in patients with HCC and other solid tumors using a classic 3+3 design. Upon identification of the RDE, a monotherapy expansion in advanced HCC patients is planned to explore the preliminary anti-tumor activity of OTX-2002. Part 2 will evaluate OTX-2002 in combination with HCC standard of care in the same HCC population as that of Part 1 expansion. The safety of OTX-2002 at the selected dose in combination with a tyrosine kinase inhibitor or immune checkpoint inhibitor will be evaluated in a safety run-in; expansion will follow to identify the preliminary anti-tumor activity of the combinations. Key eligibility criteria for HCC patients include: 1) Barcelona Clinical Liver Cancer (BCLC) stage B or C disease, 2) Child-Pugh A liver function, 3) received at least 1 prior systemic therapy. The MYCHELANGELO I study began enrollment in August 2022, and Part 1 dose escalation is ongoing in the US. References: 1. Lin et al. World J Hepatol. 2010; 2: 16–20. 2. Senapedis et al. Ann Oncol. 2022; 33: S355. Clinical trial information: NCT05497453 .
A systematic review to assess the efficacy of HER2-targeted treatment regimens in HER2-positive metastatic colorectal cancer (mCRC).
Authors: Muhammad Bakhtiar, Sepideh Gholami, Anwaar Saeed
Journal: Journal of Clinical Oncology (2023)

166 Background: Recently, there has been a breakthrough in the treatment and disease control of HER-2 positive mCRC using Trastuzumab (TRA) +Tyrosine Kinase inhibitor (TKI) regimens and regimens with trastuzumab based antibody drug conjugates (ADCs). Methods: A total of 14 randomized controlled trials and single arm clinical trials were collected from PubMed, Cochrane library, and Embase. 7 trials were excluded for being duplicate, irrelevant or because of lack of response from the trial researchers. Data from the remaining 7 articles was extracted either from the full publication or from researchers for undergoing studies. Trials using similar drug combinations were added up and results were reported cumulatively. Results: The data demonstrate an ORR of 30% or greater with the ADC, TRA deruxtecan or TRA+Tucatinib regimen with the Tucatinib combination being the most efficacious (38.10%), followed closely by the Deruxtecan ADC (36.99%). Promising disease control rate (DCR) was observed with all the combinations with TRA-Ematasin + Pertuzumab leading the charts (77.40%). TRA-Lapatinib provided the longest PFS (16.75 months) followed by TRA-Tucatinib (8.2 months) (Table). Most common treatment related adverse events (AEs) were fatigue, nausea, vomiting, diarrhea and dermatitis. More nausea/vomiting reported with TRA-deruxtecan (64.4%), while more diarrhea reported with TRA-lapatinib (81%) and TRA-tucatinib (52.3%). Dermatitis was reported mostly with TRA-lapatinib (44%) and TRA-tucatinib (17.4%). Conclusions: Our analysis shows that combination treatment with TRA-Deruxtecan and TRA-tucatinib are associated with the highest ORR and DCR in HER2+ mCRC. Long term data are needed to define clinical efficacious based on survival endpoints.[Table: see text]
A phase II study of paclitaxel and carboplatin plus PD-1 inhibitors combined with anlotinib as first-line treatment for advanced esophageal cancer.
Authors: Mingfang Xu, Yu Pu, Yuzhu Jiang, Hong Liu, Yan Feng, Chengyuan Qian, Nan Dai, Dong Wang, Mengxia Li
Journal: Journal of Clinical Oncology (2023)

395 Background: The combination of anti-PD-1 mAb with chemotherapy is one of the standard first-line therapies for advanced esophageal cancer. Recent studies have shown that anti-PD-1 mAb combined with chemotherapy or targeted treatment can improve the efficacy of immunotherapy. The purpose of this study was to evaluate the efficacy and safety of paclitaxel and carboplatin (TC) combined with anlotinib, an anti-angiogenic TKI, and anti-PD-1 mAb, in the treatment of advanced esophageal cancer. Methods: This study was a parallel, single-center, open-label, phase II trial. A total of 90 patients (pts) with previously untreated, advanced or metastatic ESCC, with an age ranging from 18-75 years old, and an ECOG performance status ≤ 1 were planned to be enrolled into three arms with an allocation ratio of 1:1:1. Arm A received paclitaxel (175 mg/m 2 , IV, d1, q3w) /nab-paclitaxel (260mg/m 2 , IV, d1, q3w) + carboplatin (AUC 4-6, IV, d2, q3w) + anti-PD-1 mAb + anlotinib (8mg, PO, d1-14, q3w); Arm B received TC with anti-PD-1 mAb; Arm C received TC only. After 4-6 cycles of induction therapy, arm A and arm B would receive anti-PD-1 mAb plus anlotinib or anti-PD-1 mAb as maintenance therapy until disease progression or intolerable adverse events, respectively. The primary endpoint was ORR. Secondary endpoints included PFS, OS and safety. Results: At data cut-off date (Sep. 20, 2022), a total of 90 pts were enrolled and 88 pts were available for efficacy assessment. 25 of 28 pts achieved partial response (PR) in arm A, 13 of 30 pts PR in arm B, and 7 of 30 pts PR in arm C. The ORR (95% CI) were 89.3% (71.8-97.7) in arm A, 43.3% (25.5-62.6) in arm B, and 23.3% (9.9-42.3) in arm C. The DCR (95% CI) were 100% (87.7-100.0) in arm A, 96.7% (82.8-99.9) in arm B, and 83.3% (65.3-94.4) in arm C. The median PFS was not reached. The rate of treatment related adverse events (TRAEs) of any grade was 100% in all three groups, and grade 3 TRAEs were 23.3%, 16.7% and 13.3%, respectively. The most common grade 3 TRAEs were thrombocytopenia (6.7%), leukopenia (5.6%), neutropenia (5.6%). No grade 4 or 5 TRAEs occurred. Conclusions: The addition of anlotinib to immunotherapy plus chemotherapy as first-line therapy for ESCC demonstrated a high ORR (89.3%), and a manageable safety profile. Clinical trial information: NCT04471480 .